Clinical and Biochemical Response to rhGH Treatment in Children with Heterozygous Variants in the IGFALS Gene.

D. BRASLAVSKY; L. MARTUCCI; A. MARTINEZ; HR. CASSINELLI; PA. SCAGLIA; MG. BALLERINI; S. DOMENE; I. BERGADA; H. JASPER; A. KESELMAN; LM. KARABATAS; M. GUTIERREZ; MG. ROPELATO; H. DOMENE

Washington D.C.

Congreso; 10th International Meeting of Pediatric Endocrinology; 2017

CLINICAL AND BIOCHEMICAL RESPONSE TO RHGH TREATMENT IN CHILDREN WITH HETEROZYGOUS VARIANTS IN THE IGFALS GENE. Ana Keselman, MD, Centro de Investigaciones Endocrinológicas ?Dr. César Bergadá? (CEDIE) CONICET ? FEI ? División de Endocrinología, Hospital de Niños "Ricardo Gutiérrez?, Buenos Aires, Argentina; Paula A Scaglia, MS/MA; Liliana M Karabatas, PhD, Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" /CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina; Braslavsky Debora, MD, Centro de Investigaciones Endocrinologicas "Dr Cesar Bergada" (CEDIE) CONICET-FEI_ Division de Endocrinologia Hospital de Niños" Ricardo Gutierrez", Buenos Aires, Argentina; Ballerini Gabriela, MS/MA, Centro de Investigaciones Endocrinologicas Dr "Cesar Bergada" (CEDIE) CONICET-FEI_ Division de Endocrinologia Hospital de NIños "Ricardo Gutierrez", Buenos Aires, Argentina; Martucci Lucia, MS/MA, Centro de Investigaciones Endocrinologicas Dr "Cesar Bergada "(CEDIE) CONICET-FEI_ Division de Endocrinologia Hospital de Niños "Ricardo Gutierrez", Buenos Aires, Argentina; Gutierrez Mariana, PhD; Domene Sabina, PhD, Centro de Investigaciones Endocrinologicas "Dr Cesar Bergada" (CEDIE) CONICET-FEI_ Division de Endocrinologia Hospital de Niños "Ricardo Gutierrez", Buenos Aires, Argentina; Martinez Alicia, MD, Centro de Investigaciones Endocrinologicas "Dr Cesar Bergada " (CEDIE) CONICET-FEI_ Division de Endocrinologia Hospital de Niños "Ricardo Gutierrez", Buenos Aires, Argentina; Ropelato Gabriela, PhD; Bergada Ignacio, MD, Centro de Investigaciones Endocrinologicas "Dr Cesar Bergada" (CEDIE) CONICET-FEI_ Division de Endocrinologia Hospital de Niños "Ricardo Gutierrez", Buenos Aires, Argentina; Hamilton R Cassinelli, MD, Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" /CEDIE), CONICET - FEI - División de Endocrinología, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina; Horacio Domene, PhD; Hector Jasper, MD, Centro de investigaciones Endocrinologicas "Dr Cesar Bergada", CEDIE-CONICET-FEI, División de Endocrinologia Hospital de Niños "Ricardo Gutierrez", Buenos Aires, ArgentinaObjectives: Acid-labile subunit (ALS) is crucial to stabilize IGF-I in circulating ternary complexes. Complete ALS deficiency is characterized by short stature, severe reduction of serum IGF-I and IGFBP-3 levels and poor response to rhGH treatment. Less information is available on the response to rhGH treatment in children heterozygous carriers for IGFALS gene variants.Aim: Evaluate auxological and biochemical responses to one year of rhGH treatment in short children homozygous wild-type (WT) or heterozygous carriers (HC) for non-synonymous IGFALS variants.Methods: Patients: Short children (height ≤ -2.5 SDS) presenting normal stimulated GH levels (GH max ≥ 4.7 ng/ml) were recruited. Six patients (5 boys, aged 6.7±2.2) had heterozygous IGFALS gene variants: 4 probably pathogenic by in silico or in vitro assessment: p.E35Gfs*17 (n=2), p.G506R (n=1), p.H128R (n=1), and 2 probably benign: p.R548W (n=1) and p.P22L (n=1). Other 6 idiopathic short stature (ISS) children (4 boys, aged 6.5±2.0) were homozygous WT. Height and IGF-I, IGFBP-3 levels were evaluated before and after one-year of rhGH treatment (dose of 0.33 mg/kg/week). ALS levels were evaluated only before treatment [HC: -1.95±-0.15 (n=6); WT: 1.57±2.00 (n=4); NS).Results: Auxological and biochemical data are shown in the Table.Conclusions: Short children HC for IGFALS variants showed a satisfactory and similar response to one year rhGH treatment compared to WT-ISS children, although with a lower increase in IGF-I levels. This suggests that short children, carriers for IGFALS variants, could be more sensitive to IGF-I, that paracrine action of locally produced IGF-I has a more important effect on linear growth, or a combination of both. The impact of rhGH treatment on adult height in carriers for IGFALS variants remains to be determined.